1. Field of the Invention
The present invention relates to a method for producing a fluorine-containing substituted compound by using a microreactor and a novel fluorine-containing substituted compound.
2. Description of the Related Art
The introduction of a fluorine atom and a fluorine-containing substituent into a molecule occupies a position essential for drug design in the fields of, for example, medicines and agricultural chemicals, because of the specific properties possessed by fluorine; examples have been reported in which the introduction of fluorine atoms into biologically active substances including biologically active peptides gives rise to, for example, the increase of the activity, the increase of the stability and the increase of the lipophilicity in the biologically active substances (see, for example, Takeo Taguchi, Synthesis and Application of Fluorine-Based Biologically Active Substances, 2005, CMC Publishing Co. Ltd.).
This is due to the mimic effect such that even a biologically active substance including carbon-hydrogen bonds partially replaced with carbon-fluorine bonds is incorporated into the metabolic system in a sterically almost indistinguishable manner because of the smallness of the size of the fluorine atom, and also due to the blocking effect such that such a biologically active substance generally hardly undergoes the metabolism in the body because of the extreme stability of the carbon-fluorine bond.
The fluorine atom has unique properties different from the properties of other atoms, typified by remarkable water repellency, oil repellency and heat resistance; accordingly, fluorine is expected to help the development of functional materials, and successful examples of such development include liquid crystal materials, and application of such functional materials to the electrolyte membranes of fuel cells (for example, see Japanese Patent Application Laid-Open (JP-A) Nos. 2010-248138, 2010-077351 and 2011-034829).
Such introduction of fluorine atoms or fluorine-containing substituents into molecules offers one of the most effective methods in designing, for example, medicines and agricultural chemicals, and in developing functional materials; thus the development of efficient synthesis methods of fluorine-containing substituted compounds has come to be regarded as important.
Currently most frequently found synthesis methods of fluorine-containing organic compounds are those methods which use as starting materials fluorine-containing compound relatively inexpensive and available in large amounts, and synthesize the target compounds by taking advantage of common organic synthesis reactions. Among such methods, those methods which take advantage of radical reactions are most common because radical reactions can form extremely simply organofluorine compound active species (radicals) from precursors such as organofluorine compounds.
There have hitherto been known methods using organofluorine compounds and organolithium compounds, and producing fluorine-containing substituted compounds on the basis of the reactions by way of fluorine-substituted lithium carbenoid species as the foregoing active species.
For example, a method is reported in which pentafluoroethyl iodide, benzaldehyde and methyllithium are added in a batch-type reactor and are allowed to react with each other (see J. Org. Chem., 1987, Vol. 52, p. 2482). In this method, the halogen-lithium exchange reaction between pentafluoroethyl iodide and methyllithium forms pentafluoroethyllithium, as a highly reactive fluorine-substituted carbenoid species, and a substitution reaction occurring between pentafluoroethyllithium and benzaldehyde as an electrophile produces the target fluorine-containing substituted compound.
Another method is also reported in which tribromofluoromethane, naphthylaldehyde and n-butyllithium are added in a batch-type reactor and are allowed to react with each other (see Bull. Chem. Soc. J., 1998, Vol. 71, p. 2903). In this method, the halogen-lithium exchange reaction between tribromofluoromethane and n-butyllithium forms dibromofluoromethyllithium, as a fluorine-substituted carbenoid species, and a substitution reaction occurring between dibromofluoromethyllithium and naphthylaldehyde as an electrophile produces the target fluorine-containing substituted compound.
The fluorine-substituted lithium carbenoid species is one of the active species highest in reactivity, but is on the other hand extremely unstable and tends to form a fluoroalkene through β-elimination. Accordingly, for the purpose of taking advantage of the unstable fluoroalkyllithium for the synthesis reaction of the fluorine-containing substituted compound, an excessive amount of fluoroalkyl halide is required, and it is required to perform the reaction under a low temperature condition of −78° C. and by allowing beforehand an electrophile exhibiting electrophilic effect to be concomitantly present in the batch-type reactor. Further, some of the fluorine-substituted lithiumcarbenoid species are unstable under a low temperature condition of −100° C., and cannot be used for the synthesis reaction of the fluorine-containing substituted compounds. Consequently, the industrial realization of the foregoing method involves extreme difficulty.
The generation of the active species (radical) depends on the strength of the reactivity between the organolithium compound and the organofluorine compound and the strength of the reactivity between the organolithium compound and the electrophile, and hence there is a problem such that such an electrophile that is higher in reactivity than the organofluorine compound used cannot be used.
Thus, according to the present state of affairs, the following methods for producing a fluorine-containing substituted compound have been awaited: a method for producing a fluorine-containing substituted compound, capable of producing a fluorine-containing substituted compound under industrially practicable temperature conditions, by using a simple apparatus and simple operations; and a method for producing a fluorine-containing substituted compound, capable of widening the range of selection of the electrophile and thus producing novel fluorine-containing substituted compounds.